Tumor associated monoclonal antibodies (mAb's) are therapeutic agents as selective carriers of cytotoxic agents to malignant cells. This hypothesis is tested in animal model systems with mAbs directed toward antigens associated with a variety of malignancies. The cytocidal agents employed are radionuclides and their relative efficacy is evaluated in appropriate murine tumor model systems. The radionuclides chosen for study span the range of radionuclidic properties available thereby permitting the assay of the effects of emission energy, half-life, and type of emission. Current research is focused on performing extensive pre-clinical studies with alpha-particle emitting radionuclides 212Pb, 213Bi, and 211At. Ongoing clinical trials currently employ the second generation bifunctional chelating agent 1B4M-DTPA (aka MX-DTPA or Tiuxetan) for sequestering 90Y and / or the CHX-A'' DTPA for 90Y and / or 213Bi. Both are suitable for scintigraphy with either 111In or PET imaging with 86Y. The chelation chemistry for 213Bi is established and is employed now is pre-clinical and clinical studies. Pre-clinical evaluation of novel bifunctional chelating agents and linkers for targeted radiotherapy with isotopes of interest continues particularly in regards to the combination of high stability with rapid formation rates for radio-lanthanides and alpha-particle emitting radionuclides such as 213Bi that are now being extended to peptides targeting receptors of interest. Studies with 211At have continued with additional pre-clinical studies with the novel reagent termed SAPS conjugated to the monoclonal antibody 7G7 in several ATL murine tumor models. Studies to assess the inclusion of a dative bond pi donor system with appropriate donor heteroatoms ortho to the 211At labeling site have been completed. Further refinements of SAPS to enhance long-term stability have also been completed. A highly extensive and focused pre-clinical investigation into the use of both 212Bi and 212Pb continues for the treatment of disseminated intraperitoneal disease such as that arising from either ovarian or pancreatic cancer. In addition to evaluation of the efficacy of these radionuclides individually with each mAb, the use of combined radiolabeled mAbs, and their combinations with chemotherapeutics continues to be systematically investigated. This investigation rests on the hypothesis that single doses of a single, targeted radionuclide lacks a rational basis for cancer therapy and that combined modality therapies will achieve significant therapeutic enhancements. Current results indicate that substantial increases in median life expectancy in murine models are possible with single doses of 213Bi or 212Pb conjugated to clinically relevant antibodies such as CC49DCH2 or Herceptin. Use of 212Pb in combination with Gemcitabine has shown impressive enhanced therapeutic efficacy; fractionated dosing of both 212Pb and Gemcitabine provided evidence that optimization of both drug combination and scheduling will result in extended survival. Studies combining administration of 213Bi or 212Pb with taxol demonstrated significant extension of survival with a very strong dependence on administration scheduling. Studies are planned for next year to obtain a greater understanding of this result thereby permitting more rational decisions in combining taxol with additional established drugs with these isotopes. Fractionation studies of 213Bi with taxol are also scheduled later this year. Preliminary investigations of the administration order impact of carboplatin combined with 212Pb are ongoing. Lastly, the combination of two non-cross-reactive mAbs, CC49DCH2 and Herceptin, both radiolabeled with 213Bi demonstrated a significant extension of survival with a very strong dependence on administration scheduling.